ORIGINAL STUDY
Clinical Characteristics and Survival of Patients With an Adult-Type Ovarian Granulosa Cell Tumor A 56-Year Single-Center Experience Saara Bryk, MD,*Þ Anniina Fa¨rkkila¨, MD, PhD,*Þ Ralf Bu¨tzow, MD, PhD,þ Arto Leminen, MD, PhD,* Markku Heikinheimo, MD, PhD,Þ§ Mikko Anttonen, MD, PhD,*Þ Annika Riska, MD, PhD,* and Leila Unkila-Kallio, MD, PhD* Objective: The objective of this study was to evaluate clinical prognostic factors and survival of patients with ovarian granulosa cell tumors (GCTs) in a long-term follow-up study. Methods: A total of 240 adult-type GCTs diagnosed in Helsinki University Central Hospital from 1956 to 2012 were histologically reevaluated. Data were analyzed for several clinical factors in relation to major developments in imaging, surgery, and chemotherapy: the old era (1956Y1983) and the new era (1984Y2012). Prognostic factors for survival were evaluated in the univariate and multivariate analyses. Results: The original diagnosis was confirmed in 187 (77.9%) patients. The International Federation of Gynecology and Obstetrics stage I disease was present in 89.2%; stage II, in 7.0%; stage III, in 3.8%; and stage IV, in 0% of cases. The mean age at diagnosis (52.9 years) and the mean tumor size (10.8 cm) did not change significantly over time. The most common presenting symptom was abnormal bleeding, but 14% were asymptomatic. The mean follow-up period was 15.7 years. Recurrence rate was similar in both eras. The GCTspecific 5-, 10-, and 20-year survival rates were 95.6%, 88.1%, and 79.8% in the old era as well as 97.2%, 94.8%, and 94.8% in the new era, respectively. In the univariate analyses, old era, patient age older than 60 years, tumor size greater than 10 cm, advanced stage, residual tumor, and use of hormonal adjuvant treatment were associated with GCT-related deaths. Prior use of oral contraceptives and history of infertility improved survival rates. In the multivariate analysis, stage was the only independent prognostic factor for GCT-specific survival. Conclusions: An accurate histological diagnosis of GCT is essential. Stage IV disease is an extreme rarity. However, tumor stage overcomes other possible clinical prognostic factors for GCT-specific survival. Fertility-sparing surgery, the use of oral contraceptives, or hormonal replacement therapy seems not to be risk factors for survival. Key Words: Granulosa cell tumor, Ovarian cancer, Survival, Prognostic factors Received June 6, 2014, and in revised form September 10, 2014. Accepted for publication September 11, 2014. (Int J Gynecol Cancer 2015;25: 33Y41) *Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, †Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, and ‡Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland; and §Department of Pediatrics, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, MO.
Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000304 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Leila Unkila-Kallio, MD, PhD, Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, PO Box 140, 00290 Helsinki, Finland. E-mail: [email protected]. Supported by Sladjana M. Crosley Fund for GCT Research as well as the Sigrid Juselius Foundation and Helsinki University Central Hospital Research Funds. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).
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cell tumors (GCTs) are rare malignancies acG ranulosa counting for 3% to 5% of all ovarian tumors. Granulosa 1
cell tumors include both adult and juvenile types with distinct histological and clinical features. The adult type of GCTs is more common,2 representing 95% of all GCTs and typically occurs in perimenopause or early postmenopause.1,3 These tumors arise from the sex-cord stromal cells of the ovary and are potentially estrogen-secreting. Hormonal secretion can lead to symptoms such as metrorrhagia or postmenopausal bleeding, and GCTs have also been associated with infertility.4 As a result of hyperestrogenism, endometrial pathology appears in 26% to 76% of patients.1Y3,5,6 The histological diagnosis of GCT has proven to be demanding, reaching more than 50% in the rate of false positives when reevaluated.7 Surgery is the primary treatment of GCTs and includes hysterectomy, bilateral adnexectomy, and omentectomy as well as biopsies from peritoneal surfaces.8 The necessity for lymphadenectomy has varied over the decades and is not currently recommended.8 The role of adjuvant therapy is unclear, although in advanced-stage disease, platinum-based chemotherapy is nowadays recommended.8Y10 For premenopausal patients, fertility-sparing surgery is an option.2,6,7 Previously, tumor stage, tumor size, patient age, presence of tumor rupture, and histological features have been suggestions for potential prognostic factors.1Y3,5,11 Only the International Federation of Gynecology and Obstetrics (FIGO) stage has, however, shown consistent prognostic significance.2,5Y7,11Y14 Compared with epithelial cancer, GCTs are usually diagnosed at an early stage and have a relatively favorable prognosis with a 10-year survival up to 95%.12 Nevertheless, 10% to 34% of cases recur,2,3,5,6,12,15 even after several decades. Once the tumor has recurred, prognosis significantly deteriorates.5 Because of the rarity of GCTs, studies are scarce and have relatively small sample sizes and/or short follow-up periods.1,2,6,12,14,16 Many of the older studies also include both juvenile- and adult-type tumors,1,3,5,14,16 and histological reevaluation has not always been performed.2,6,12,14 The aims of this study were to evaluate the clinical characteristics, diagnosis, and treatment of GCTs and study the clinical factors affecting survival as well as to determine whether the major changes over time in diagnostics, surgery, and chemotherapy have influenced these factors. This study’s assets are the 5decade-long study period in a single institute with a large, partly prospective patient series of histologically reconfirmed adult-type GCTs.
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evaluation of original pathology reports and clinical data in addition to consensus by a gynecologic oncologist and a gynecologic pathologist. Two cases of primary extraovarian tumors were excluded. After the reevaluation of original diagnoses, a total of 187 patients were eligible for analysis (Fig. 1). The study covers both retrospective and prospective patient groups. Since October 2007, patients with suspected or diagnosed GCT as well as those in follow-up (n = 97) have been recruited with their informed consent for a prospective long-term follow-up study with a structured interview on hormonal and reproductive factors and family cancer. If the patients were no longer involved in routine follow-up, they received an invitation for a similar interview and clinical examination with a vaginal scan every 5 years. For all patients, detailed data were collected from medical records for age, body mass index (BMI), menarcheal age, menopausal status, parity, use of hormonal therapy or oral contraceptives, history of infertility and second or family cancer, main symptoms, tumor characteristics (size, stage, presence of tumor rupture, ascites, residual tumor), endometrial pathology, treatment, and pathology reports. The follow-up information included details on follow-up visits performed at HUCH or other units, recurrences, and survival. Survival data were obtained from the Finnish national population register on December 27, 2012, and from death certificates including diagnosis of the cause of death from the Statistics Finland. The clinical data were collected into a database using FileMaker Pro 11.0v4 (FileMaker, Inc, Santa Clara, CA). To study the effects of improved diagnostics, surgical techniques, and chemotherapy, the data were divided into 2 groups according to the time of diagnosis: 1956Y1983 and 1984Y2012, corresponding to the ‘‘old’’ and ‘‘new’’ era, respectively. The new era is characterized by the introduction of platinum-based chemotherapy and improved staging surgery as well as increased use of vaginal ultrasonography and computed tomographic scans in our unit. Because many of the patients (n = 19) had a history of previous hysterectomy,
MATERIALS AND METHODS Patients The ethics committee of Helsinki University Central Hospital (HUCH) and the National Supervisory Authority for Welfare and Health approved the study. A total of 240 women were diagnosed with GCT in HUCH in 1956Y2012. Helsinki University Central Hospital is a tertiary hospital responsible for the cancer treatment of 1.5 million inhabitants in Southern Finland. An expert gynecologic pathologist (R.B.) reviewed all available histologic samples to confirm the diagnosis of GCT. Of the patients with no available sample (n = 14), a total of 3 cases were included in the study on the basis of a thorough
34
FIGURE 1. Flow chart of the patients included in the study. All patients with GCT diagnosed at HUCH from 1956 to 2012 were initially enrolled, histologically reevaluated, and divided into 2 eras according to the introduction of platinum-based chemotherapy in 1984. Altogether, 53 patients were excluded from the study. * 2014 IGCS and ESGO
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surgery was considered complete if no gynecological organs were left and incomplete if an adnexa and/or uterus were preserved. Fertility-sparing surgery was defined as the preservation of the uterus and 1 ovary in a patient younger than 45 years. The definition of staging surgery included cases where peritoneal biopsies and omental biopsy or omentectomy were performed. Adjuvant hormonal treatment was equivalent to a high-dose medroxyprogesterone acetate. Determination of tumor stage was based on the FIGO 2009 criteria.17 Recurrence was recorded only in patients having no residual tumor after surgery or after chemotherapy, the latter being dependent upon a clean computed tomographic
Factors of Survival in Adult-Type GCT
scan or a second-look operation. Otherwise, patients were not considered disease-free after primary treatment.
Statistical Analysis Statistical analysis was performed using JMP Pro 10.0.2 (SAS Institute Inc, Cary, NC). The Pearson W2 test or Fisher exact test was used to test associations between the groups. Continuous variables were analyzed for normal distribution with the Shapiro-Wilk test and compared with a parametric (Student t test) or a nonparametric test (Mann-Whitney) when appropriate. The survival curves and estimates were obtained using the Kaplan-Meier method, compared using the log-rank
TABLE 1. Clinical characteristics of the patients with GCT according to time of diagnosis
Characteristic (Patients With Data Available) Age, y (n = 187) G60 960 Menarche (n = 165) G14 Q14 Menopausal status (n = 184) Premenopausal Postmenopausal Parity (n = 185) Nulliparous Primiparous Multiparous Infertility (n = 178) Yes No HRT (n = 133) Yes No OC (n = 138) Yes No Initial symptoms (n = 186) Abnormal bleeding Abdominal pain Abdominal distension General symptoms Asymptomatic Preoperative imaging (n = 183) Ultrasonography Computed tomographic scan
1956Y1983 The Old Era
1984Y2012 The New Era
Total N = 187
n = 70
n = 117
n (%)
48 (68.6%) 22 (31.4%)
79 (67.5%) 38 (32.5%)
127 (67.9) 60 (32.1)
ns
24 (40.0%) 36 (60.0%)
64 (61.0%) 41 (39.0%)
88 (53.3) 77 (46.7)
0.01
27 (39.1%) 42 (60.9%)
46 (40.0%) 69 (60.0%)
73 (39.7) 111 (60.3)
ns
23 (33.3%) 16 (23.2%) 30 (43.5%)
41 (35.3%) 22 (19.0%) 53 (45.7%)
64 (34.6) 38 (20.5) 83 (44.9)
ns
7 (10.6%) 59 (89.4%)
20 (17.9%) 92 (82.1%)
27 (15.2) 151 (84.8)
ns
4 (10.5%) 34 (89.5%)
21 (22.1%) 74 (77.9%)
25 (18.8) 108 (81.2)
ns
9 (17.0%) 44 (83.0%)
48 (56.5%) 37 (43.5%)
57 (41.3) 81 (58.7)
G0.0001
40 (58.0%) 12 (17.4%) 12 (17.4%) 0 (0.0%) 5 (7.2%)
43 36 14 3 21
(36.7%) (30.8%) (12.0%) (2.6%) (17.9%)
83 (44.6) 48 (25.8) 26 (14.0) 3 (1.6) 26 (14.0)
0.005
104 (91.2%) 2 ( 1.8%)
115 (62.8) 2 (1.1)
G0.0001 ns
11 (15.9%) 0 (0.0%)
Difference Between the Eras, P
HRT, hormone replacement therapy; ns, not significant; OC, oral contraceptives.
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test, and displayed leaving minimum of 5 subjects at risk. The univariate and multivariate analyses were conducted with the Cox regression model; only significant variables in the univariate tests were included in the multivariate models. For stage I analysis, clinically relevant variables were included in the univariate and multivariate models. A P value of less than 0.05 was considered significant.
RESULTS Histological Reevaluation Adult GCT was histologically reconfirmed in 187 (77.9%) patients (Fig. 1). The revised diagnoses of the 40 (16.7%; 23% in the old era, 12% in the new era) tumors are presented in Supplementary Table 1 (available as Supplemental Digital Content at http://links.lww.com/IGC/A236). From original stage distribution, 15.8% (n = 31) of stage I, 2.3%
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(n = 3) of stage II, 53.3% (n = 8) of stage III, and 100.0% (n = 4) of stage IV tumors were excluded from the analysis.
Patient Characteristics The clinical characteristics of patients with GCT according to the 2 eras are summarized in Table 1. The mean age at diagnosis in the whole series was 52.9 years (range, 18Y87 years), and there was no significant difference between the eras. The median menarcheal age was 13 years (range, 9Y20 years) and was significantly lower in the new era (P = 0.02). The median BMI was 26 kg/m2 (range, 14.3Y45.3 kg/m2). The use of both oral contraceptives and hormone replacement therapy was more frequent in the new era, but only the use of oral contraceptives was significant (P G 0.0001). The presenting symptoms were most commonly menstrual cycle disturbances or postmenopausal bleeding in both eras (44.6%). Altogether, 114 women (61.0%) experienced abnormal bleeding patterns. Of all patients, 26 (14.0%) were
TABLE 2. Primary tumor characteristics of the patients with GCT according to time of diagnosis
Characteristic (Patients With Data Available) Tumor size (n = 179) G10 cm Q10 cm Tumor location (n = 187) Right ovary Left ovary Bilateral Ascites* (n = 166) Yes No Tumor rupture† (n = 180) Yes No Stage (n = 185) I II III Endometrial pathology (n = 157) Polyps Hyperplasia Carcinoma No pathology Histological subtype (n = 161) Follicular/trabeculoid Diffuse/sarcomatoid
1956Y1983 (The Old Era)
1984Y2012 (The New Era)
Total N = 187
n = 70
n = 117
n (%)
26 (39.4%) 40 (60.6%)
57 (50.4%) 56 (49.6%)
83 (46.4) 96 (53.6)
ns
33 (47.1%) 35 (50.0%) 2 (2.9%)
60 (51.3%) 54 (46.2%) 3 (2.6%)
93 (49.7) 89 (47.6) 5 (2.7)
ns
12 (17.9%) 55 (82.1%)
26 (26.3%) 73 (73.7%)
38 (22.9) 128 (77.1)
ns
15 (23.8%) 48 (76.2%)
49 (41.9%) 68 (58.1%)
64 (35.6) 116 (64.4)
0.016
60 (88.2%) 4 (5.9%) 4 (5.9%)
105 (89.7%) 9 (7.7%) 3 (2.6%)
165 (89.2) 13 (7.0) 7 (3.8)
ns
5 36 3 20
(7.8%) (56.2%) (4.7%) (31.3%)
17 (18.3%) 25 (26.9%) 8 (8.6%) 43 (46.2%)
19 (32.2%) 40 (67.8%)
42 (41.2%) 60 (58.8%)
22 61 11 63
Difference Between the Eras, P
(14.0) (38.9) (7.0) (40.1)
0.003
61 (37.9) 100 (62.1)
ns
*Positive cytology, n = 5. †Spontaneous or iatrogenic. ns, not significant.
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asymptomatic and diagnosed during routine gynecological examination or imaging procedures. In the new era, the proportion of asymptomatic patients was higher, whereas those with abdominal distension were fewer (P = 0.03). Of the 26 patients with abdominal distension, 24 had a large tumor (910 cm), 19 had ascites at the time of diagnosis, and 6 patients experienced tumor rupture.
Tumor Characteristics Tumor characteristics are reported in Table 2. The median tumor size was 10.0 cm (mean, 10.8 cm; range, 0.5Y30 cm). Ascites was present in 38 patients (22.9%) at the time of surgery, but cytology was positive only in 5 cases. Either spontaneous or iatrogenic tumor rupture occurred significantly more often in the new era (P = 0.02). Of all the 48 ruptures in the new era, 18 were spontaneous and 30 occurred during surgery. Twenty (41.7%) of these were laparoscopic procedures. The majority of the patients had stage I disease (165 cases, 89.2%) without significant variation over time. There were no stage IV cases present in the data.
Factors of Survival in Adult-Type GCT
Endometrial pathology occurred in 94 patients (59.9% of those evaluated), with a significant difference between the eras (P = 0.003): endometrial hyperplasia was less common and polyps were more common in the new era, whereas endometrial cancer occurred quite similarly between the 2 eras. Any other cancer before, at, or after GCT diagnosis was discovered in 20.9% of all patients with the available data, with no significant differences in the 2 eras. The most common other cancers were endometrial (n = 11, 6.7%) and breast (n = 9, 5.5%) cancer. History of cancer in a first-degree relative was found in 50.0%, with breast cancer being the most common (22.0%).
Treatment Characteristics All patients underwent surgical treatment (Table 3). The majority of the patients (78.0%) had complete surgery, and the presence of residual tumor was similar in both eras. Staging surgery and lymphadenectomy or lymph node biopsy were performed only in the new era (P G 0.001). Fertilitysparing surgery took place in 16.8% of cases. Surgery as the
TABLE 3. Treatment characteristics of primary GCT according to time of diagnosis
Characteristic (Patients With Data Available) Initial surgery (n = 186) Complete* Incomplete Staging surgery Lymphadenectomy† Residual tumor (n = 183) Yes No Treatment modality (n = 186) Surgery only Surgery + CT Surgery + RT Surgery + CT + RT Chemotherapy (n = 187) Nonplatinum-based CT Platinum-based CT Adjuvant hormonal therapy‡ (n = 187) Yes No Second-look operation (n = 187) Yes No
1956Y1983 The Old Era
1984Y2012 The New Era
Total (%)
n = 70
n = 117
n = 187
57 12 0 0
(82.6%) (17.4%) (0.0%) (0.0%)
88 (75.2%) 29 (24.8%) 52 (44.4%) 41 (35.3%)
3 (4.4%) 66 (95.6%)
3 (2.6%) 111 (97.4%)
42 7 11 9
145 41 52 41
(78.0) (22.0) (28.1) (22.2)
6 (3.3) 177 (96.7) 141 22 13 10
(75.8) (11.8) (7.0) (5.4)
Difference Between the Eras, P ns G0.0001 G0.0001 ns
G0.0001
(60.9%) (10.1%) (15.9%) (13.0%)
99 (84.6%) 15 (12.8%) 2 (1.7%) 1 (0.9%)
16 (22.9%) 0 (0.0%)
1 (0.9%) 15 (12.8%)
17 (9.1) 15 (8.0)
G0.0001
12 (17.1%) 58 (82.9%)
1 (0.9%) 116 (99.2%)
13 (6.9) 174 (93.1)
G0.0001
7 (10.0%) 63 (90.0%)
11 (9.4%) 106 (90.6%)
18 (9.6) 169 (90.4)
ns
*No gynecological organs (adnexa or uterus) left after initial treatment. †Lymph node biopsy or lymphadenectomy. ‡A high-dose medroxyprogesterone acetate. CT, chemotherapy; ns, not significant; RT, radiotherapy.
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only treatment became more common in the new era. Adjuvant treatment was given to a total of 45 patients, including chemotherapy (n = 32), adjuvant hormonal treatment (n = 13), and radiotherapy (n = 23), with some of the treatment methods overlapping. In the new era, pelvic radiotherapy was given to 3 patients, once solely for GCT in 1984 and twice for GCT and a simultaneous endometrial carcinoma. Similarly, only 1 elderly patient with inoperable GCT received hormonal adjuvant therapy in the new era. Postoperative platinum-based chemotherapy was given to 15 patients in the new era, of whom 5 had stage IC and 6 stage IIYIII diseases. Second-look operation was common from 1970 to 1998 and was performed on 10% of all patients in the series.
Outcomes and Survival Analysis The mean follow-up period was 15.6 years (median, 13.7 years; range, 0.01Y50.7 years) in the total study group. The follow-up was significantly longer in the old era (mean, 22.1; median, 22.4; range, 0.7Y50.7) than in the new era (mean, 11.5 years; median, 10.3; range, 0.01Y27.8; P G 0.0001), as expected. A total of 24 patients (23.8%) had less than 5 years of follow-up data in the new era. At the end of the follow-up, 113 patients (60.4%) were alive, 27 (14.4%) had died of GCT, and 46 (24.6%) had died of other causes. One patient was lost to follow-up. In total, 127 patients (68.6%) were free of the disease during the whole study period. Recurrence was observed in a total of 54 patients (29.2%). In the old era, the rate of recurrence was 35.7%, whereas the rate was 25.2% in the new era (P = 0.11). The median time to the first recurrence was 7.0 years (range,
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1.0Y32.5). A total of 9 patients were alive with recurrence at the end of the follow-up. In the whole series, the overall 5-, 10-, and 20-year survival rates were 94.4%, 87.1%, and 67.1%, respectively (Supplementary Fig. 1, available as Supplemental Digital Content at http://links.lww.com/IGC/A237). The GCT-specific 5-, 10-, and 20-year survival rates were 96.7%, 91.8%, and 87.1%. In the old era, GCT-specific 5-, 10-, and 20-year survival rates were 95.6%, 88.1%, and 79.8% as well as 97.2%, 94.8%, and 94.8% in the new era, respectively. In the univariate Cox regression analysis, decreased overall survival was associated with patient age older than 60 years, old era, menarcheal age older than 14 years, postmenopausal status, presence of symptoms, advanced stage, complete surgery, presence of residual tumor, and use of hormonal adjuvant therapy, whereas history of infertility and use of oral contraceptives were associated with a more favorable outcome (data not shown). In the multivariate analysis, patient age older than 60 years, old era, advanced stage, and presence of residual tumor were the factors that remained significant. The GCT-related deaths were associated with diagnosis in the old era as well as patient age older than 60 years, tumor size greater than 10 cm, advanced stage, presence of residual tumor after initial surgery, and use of hormonal adjuvant therapy (Table 4). Patient age was also significant when analyzed as a continuous variable, but tumor size was not (data not shown). The use of oral contraceptives and history of infertility before diagnosis improved GCT-related survival. However, in the multivariate analysis, only higher stage (II-III vs I) remained significant. In addition, KaplanMeier curves illustrate survival outcomes (Fig. 2). The use
TABLE 4. The Cox regression models for GCTYspecific survival Prognostic Factors in the Multivariate Analysis
GCT-Specific Survival Prognostic Factors in the Univariate Analysis Factor Infertility Use of OC Stage IIYIII vs stage I Residual tumor Hormonal adjuvant Age 960 y Old era Tumor size Q10 cm
HR
95% CI
P
HR
95% CI
P
0.20 0.33 16.19 10.98 3.64 2.82 2.68 2.43
0.01Y0.93 0.08Y0.99 6.26Y43.42 3.09Y31.08 1.33Y8.52 1.16Y6.73 1.07Y7.63 1.02Y6.68
0.04 0.05 G0.0001 0.0009 0.02 0.02 0.04 0.04
0.80 0.85 10.51 1.71 3.33 1.07 2.17 3.10
0.04Y5.56 0.16Y3.77 1.65Y69.48 0.18Y13.97 0.80Y12.37 0.20Y4.90 0.40Y18.44 0.75Y21.07
ns ns 0.01 ns ns ns ns ns
Prognostic Factors in the Multivariate Analysis
Stage I GCT-Specific Survival Prognostic Factors in the Univariate Analysis Factor
HR
95% CI
P
HR
95% CI
P
Age 960 y Stage IB or C vs stage IA Tumor size 910 cm
2.54 1.96 1.85
0.64Y8.72 0.69Y5.38 0.62Y6.79
ns ns ns
2.37 1.56 1.72
0.60Y8.18 0.49Y4.79 0.54Y6.50
ns ns ns
CI, confidence interval; HR, hazard ratio; OC, oral contraceptives.
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Factors of Survival in Adult-Type GCT
FIGURE 2. Kaplan-Meier curves of GCT-specific survival according to time of diagnosis (A), age at diagnosis (B), tumor size (C), tumor stage (D), treatment with platinum versus nonplatinum-based chemotherapy (E), and presence of residual tumor (F). All curves are illustrated leaving a minimum of 5 patients at risk at the end of the horizontal axis. of platinum-based chemotherapy (Fig. 2E) and lack of symptoms were associated with a more favorable outcome but could not be included in the Cox regression analyses because of the absence of GCT-associated deaths in these groups. To further study the effects of platinum-based treatment, we conducted a univariate Cox regression analysis after excluding all patients treated with chemotherapy and found no
statistically significant difference in GCT-related survival between the new and old era groups (data not shown). In a separate analysis including only stage I tumors, there were no significant variables associated with GCTspecific survival (Table 4). Also, there were no differences in GCT-specific or overall survival related to BMI, parity, history of second or family cancer, use of hormone replacement
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therapy before or after diagnosis, endometrial pathology, staging surgery, lymphadenectomy, or tumor rupture.
DISCUSSION The long natural course of GCT requires decades of follow-up to provide reliable information on its behavior, especially on survival.12 The mean follow-up time of 15.6 years, or 187 months, in our study is remarkably longer than that in other recent publications.2,6,12,13 Even for the new era patients alone, the mean follow-up time of 11.5 years was reached. Only 1 patient was lost to follow-up 32 years after the diagnosis. The histological reevaluation excluded more than 20% of original diagnoses and changed stage distribution notably by removing more than 50% of stage III and all stage IV tumors from the study. This demonstrates the need for histological reevaluation to obtain reliable data, even in a single-institute study. Furthermore, the distinction between adult- and juveniletype GCTs is crucial, and these tumors should always be analyzed separately. The analysis of forkhead box protein L2 (FOXL2) mutation status is a promising new tool for accurate GCT diagnosis in difficult cases.18 We studied a large number of clinical prognostic factors related to GCT survival for more than 5 decades in relation to major developments in diagnostics, surgery, and chemotherapy. By performing a short structured interview in the prospective part of the study on both new and old era patients, we were able to fill in incomplete data on hormonal and reproductive history and evaluate the effects of oral contraceptives and postmenopausal hormone therapy on GCT prognosis. These have not been previously studied, although Boyce et al19 found in their epidemiological work that the use of oral contraceptives decreased the risk for developing GCT. There is also evidence linking infertility but not infertility treatments with GCT.4 The study’s infertility rate of 15.1% does not differ from population-based reference data,20 and in univariate analyses, infertility had a positive effect on survival, which was independent of the era. This suggests that hormonal therapy given for contraceptive use, infertility, postmenopausal symptoms, or treatment of bleeding disturbances is not harmful in terms of GCT-related survival. Overall, the clinical characteristics of patients with GCT have not changed over time. The earlier menarcheal age evident in the new era is a well-known phenomenon.21 Interestingly, in our data, tumor ruptures increased over time. A possible explanation is the growing number of laparoscopic procedures and, in some of the cases, an urgent surgery performed due to acute symptoms and without initial suspicion of malignancy. However, tumor rupture did not affect survival. In most studies, stage has remained the most important prognostic factor. This was confirmed in our series. Furthermore, there were no statistically significant clinical prognostic factors in stage I subanalysis, underscoring the need for molecular prognostic factors. Recently, we reported high-level nuclear atypia and high-level protein expression of GATA binding protein 4 (GATA4) as prognostic factors for GCT recurrence and survival, also in early-stage GCTs, in a subcohort of this patient series.22 Similarly to the study of Ayhan et al,6 we found that patient age older than 60 years was a significant factor in
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univariate but not in multivariate analysis, also when analyzed as a continuous variable. Tumor size had no independent effect on survival. The number of patients with residual disease was very small, so reliable conclusions of its prognostic value cannot be made. Conservative or fertility-sparing surgery did not affect outcome negatively. These results confirm those from earlier studies.2,6,7 Lymphadenectomy or lymph node biopsy was not of prognostic value in our series, as also Park et al8 and Mangili et al12 have reported. The first platinum-based chemotherapy in this study was administered in 1984, and diagnosis in the old era was associated with poorer outcome. Furthermore, the use of platinum-based treatment had a more favorable outcome when compared with nonplatinum treatment. Benefits of platinum-based treatment have been reported in several studies,8,10,23 and similar to our results, Savage et al23 found no response to nonplatinum-based chemotherapeutic agents or hormonal adjuvant therapy in the management of advanced GCT. Currently, BEC-regimen (bleomycin, etoposide, carboplatin) is the first-line chemotherapy at our institution, followed by paclitaxel-carboplatin as the secondline treatment. The survival rates in our study, especially in the new era, were among the highest in the literature, further confirming the overall favorable prognosis of GCTs. However, these tumors are known to develop late recurrences, also in the earlystage disease. Recurrence rates have varied between 10% and 34% as well as reached 29% in our study with confirmed diagnosis of GCT. The long time span of our study is both a strength and a weakness. We sought to take into account the development of diagnostic and treatment methods that might have affected the outcome. The inclusion of both retrospective and prospective data might have caused a potential bias because detailed information on, for example, hormonal therapy is focused on the latter group. Taken together, the accurate histological diagnosis of GCT is essential. In this large series of mostly early-stage GCTs, tumor stage remains the single most important prognostic factor affecting GCT-specific survival. The prognosis of GCT nowadays is excellent. Conservative or fertility-sparing surgery does not compromise survival, and the modern era with better diagnostics and treatments, including platinum-based chemotherapy, is associated with a more favorable outcome. Nevertheless, one-third of patients still develop disease recurrence, which calls for a long clinical follow-up and further detailed studies focusing on recurrent tumors.
ACKNOWLEDGMENTS The authors thank Ms Teija Karkkulainen, Mr Qiu Ge, and Mrs Anne Reijula for their excellent technical assistance.
REFERENCES 1. Malmstrom H, Hogberg T, Risberg B, et al. Granulosa cell tumors of the ovary: prognostic factors and outcome. Gynecol Oncol. 1994;52:50Y55. 2. Lee IH, Choi CH, Hong DG, et al. Clinicopathologic characteristics of granulosa cell tumors of the ovary: a * 2014 IGCS and ESGO
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3.
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11. 12.
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multicenter retrospective study. J Gynecol Oncol. 2011;22: 188Y195. Fox H, Agrawal K, Langley FA. A clinicopathologic study of 92 cases of granulosa cell tumor of the ovary with special reference to the factors influencing prognosis. Cancer. 1975;35:231Y241. Unkila-Kallio L, Tiitinen A, Wahlstrom T, et al. Reproductive features in women developing ovarian granulosa cell tumour at a fertile age. Hum Reprod. 2000;15:589Y593. Evans A, Gaffey T, Malkasian G, et al. Clinicopathologic review of 118 granulosa and 82 theca cell tumors. Obstet Gynecol. 1980;55:231Y248. Ayhan A, Salman MC, Velipasaoglu M, et al. Prognostic factors in adult granulosa cell tumors of the ovary: a retrospective analysis of 80 cases. J Gynecol Oncol. 2009;20:158Y163. Cronje HS, Niemand I, Bam RH, et al. Review of the granulosa-theca cell tumors from the Emil Novak ovarian tumor registry. Am J Obstet Gynecol. 1999;180:323Y327. Park JY, Jin KL, Kim DY, et al. Surgical staging and adjuvant chemotherapy in the management of patients with adult granulosa cell tumors of the ovary. Gynecol Oncol. 2012;125:80Y86. Homesley HD, Bundy BN, Hurteau JA, et al. Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group study. Gynecol Oncol. 1999;72:131Y137. Pautier P, Gutierrez-Bonnaire M, Rey A, et al. Combination of bleomycin, etoposide, and cisplatin for the treatment of advanced ovarian granulosa cell tumors. Int J Gynecol Cancer. 2008;18:446Y452. Bjorkholm E, Silfversward C. Prognostic factors in granulosa-cell tumors. Gynecol Oncol. 1981;11:261Y274. Mangili G, Ottolina J, Gadducci A, et al. Long-term follow-up is crucial after treatment for granulosa cell tumours of the ovary. Br J Cancer. 2013;109:29Y34.
Factors of Survival in Adult-Type GCT
13. Sun HD, Lin H, Jao MS, et al. A long-term follow-up study of 176 cases with adult-type ovarian granulosa cell tumors. Gynecol Oncol. 2012;124:244Y249. 14. Ohel G, Kaneti H, Schenker JG. Granulosa cell tumors in Israel: a study of 172 cases. Gynecol Oncol. 1983;15: 278Y286. 15. Miller BE, Barron BA, Wan JY, et al. Prognostic factors in adult granulosa cell tumor of the ovary. Cancer. 1997;79: 1951Y1955. 16. Norris HJ, Taylor HB. Prognosis of granulosa-theca tumors of the ovary. Cancer. 1968;21:255Y263. 17. FIGO Committee on Gynecologic Oncology. Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet. 2009;105:3Y4. 18. Kommoss S, Gilks CB, Penzel R, et al. A current perspective on the pathological assessment of FOXL2 in adult-type granulosa cell tumours of the ovary. Histopathology. 2014;64:380Y388. 19. Boyce EA, Costaggini I, Vitonis A, et al. The epidemiology of ovarian granulosa cell tumors: a case-control study. Gynecol Oncol. 2009;115:221Y225. 20. Rantala ML, Koskimies AI. Infertility in women participating in a screening program for cervical cancer in Helsinki. Acta Obstet Gynecol Scand. 1986;65:823Y825. 21. Anderson SE, Must A. Interpreting the continued decline in the average age at menarche: results from two nationally representative surveys of U.S. girls studied 10 years apart. J Pediatr. 2005;147:753Y760. 22. Farkkila A, Andersson N, Bu¨tzow R, et al. HER2 and GATA4 are new prognostic factors for ovarian granulosa cell tumor: a long-term follow-up study. Cancer Med. 2014;3:526Y536. 23. Savage P, Constenla D, Fisher C, et al. Granulosa cell tumours of the ovary: demographics, survival and the management of advanced disease. Clin Oncol (R Coll Radiol). 1998;10: 242Y245.
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41
Clinical Characteristics and Survival of Patients With an Adult-Type Ovarian Granulosa Cell Tumor A 56-Year Single-Center Experience Saara Bryk, MD,*Þ Anniina Fa¨rkkila¨, MD, PhD,*Þ Ralf Bu¨tzow, MD, PhD,þ Arto Leminen, MD, PhD,* Markku Heikinheimo, MD, PhD,Þ§ Mikko Anttonen, MD, PhD,*Þ Annika Riska, MD, PhD,* and Leila Unkila-Kallio, MD, PhD* Objective: The objective of this study was to evaluate clinical prognostic factors and survival of patients with ovarian granulosa cell tumors (GCTs) in a long-term follow-up study. Methods: A total of 240 adult-type GCTs diagnosed in Helsinki University Central Hospital from 1956 to 2012 were histologically reevaluated. Data were analyzed for several clinical factors in relation to major developments in imaging, surgery, and chemotherapy: the old era (1956Y1983) and the new era (1984Y2012). Prognostic factors for survival were evaluated in the univariate and multivariate analyses. Results: The original diagnosis was confirmed in 187 (77.9%) patients. The International Federation of Gynecology and Obstetrics stage I disease was present in 89.2%; stage II, in 7.0%; stage III, in 3.8%; and stage IV, in 0% of cases. The mean age at diagnosis (52.9 years) and the mean tumor size (10.8 cm) did not change significantly over time. The most common presenting symptom was abnormal bleeding, but 14% were asymptomatic. The mean follow-up period was 15.7 years. Recurrence rate was similar in both eras. The GCTspecific 5-, 10-, and 20-year survival rates were 95.6%, 88.1%, and 79.8% in the old era as well as 97.2%, 94.8%, and 94.8% in the new era, respectively. In the univariate analyses, old era, patient age older than 60 years, tumor size greater than 10 cm, advanced stage, residual tumor, and use of hormonal adjuvant treatment were associated with GCT-related deaths. Prior use of oral contraceptives and history of infertility improved survival rates. In the multivariate analysis, stage was the only independent prognostic factor for GCT-specific survival. Conclusions: An accurate histological diagnosis of GCT is essential. Stage IV disease is an extreme rarity. However, tumor stage overcomes other possible clinical prognostic factors for GCT-specific survival. Fertility-sparing surgery, the use of oral contraceptives, or hormonal replacement therapy seems not to be risk factors for survival. Key Words: Granulosa cell tumor, Ovarian cancer, Survival, Prognostic factors Received June 6, 2014, and in revised form September 10, 2014. Accepted for publication September 11, 2014. (Int J Gynecol Cancer 2015;25: 33Y41) *Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, †Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, and ‡Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland; and §Department of Pediatrics, Washington University School of Medicine, St Louis Children’s Hospital, St Louis, MO.
Copyright * 2014 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000304 International Journal of Gynecological Cancer
Address correspondence and reprint requests to Leila Unkila-Kallio, MD, PhD, Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, PO Box 140, 00290 Helsinki, Finland. E-mail: [email protected]. Supported by Sladjana M. Crosley Fund for GCT Research as well as the Sigrid Juselius Foundation and Helsinki University Central Hospital Research Funds. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).
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cell tumors (GCTs) are rare malignancies acG ranulosa counting for 3% to 5% of all ovarian tumors. Granulosa 1
cell tumors include both adult and juvenile types with distinct histological and clinical features. The adult type of GCTs is more common,2 representing 95% of all GCTs and typically occurs in perimenopause or early postmenopause.1,3 These tumors arise from the sex-cord stromal cells of the ovary and are potentially estrogen-secreting. Hormonal secretion can lead to symptoms such as metrorrhagia or postmenopausal bleeding, and GCTs have also been associated with infertility.4 As a result of hyperestrogenism, endometrial pathology appears in 26% to 76% of patients.1Y3,5,6 The histological diagnosis of GCT has proven to be demanding, reaching more than 50% in the rate of false positives when reevaluated.7 Surgery is the primary treatment of GCTs and includes hysterectomy, bilateral adnexectomy, and omentectomy as well as biopsies from peritoneal surfaces.8 The necessity for lymphadenectomy has varied over the decades and is not currently recommended.8 The role of adjuvant therapy is unclear, although in advanced-stage disease, platinum-based chemotherapy is nowadays recommended.8Y10 For premenopausal patients, fertility-sparing surgery is an option.2,6,7 Previously, tumor stage, tumor size, patient age, presence of tumor rupture, and histological features have been suggestions for potential prognostic factors.1Y3,5,11 Only the International Federation of Gynecology and Obstetrics (FIGO) stage has, however, shown consistent prognostic significance.2,5Y7,11Y14 Compared with epithelial cancer, GCTs are usually diagnosed at an early stage and have a relatively favorable prognosis with a 10-year survival up to 95%.12 Nevertheless, 10% to 34% of cases recur,2,3,5,6,12,15 even after several decades. Once the tumor has recurred, prognosis significantly deteriorates.5 Because of the rarity of GCTs, studies are scarce and have relatively small sample sizes and/or short follow-up periods.1,2,6,12,14,16 Many of the older studies also include both juvenile- and adult-type tumors,1,3,5,14,16 and histological reevaluation has not always been performed.2,6,12,14 The aims of this study were to evaluate the clinical characteristics, diagnosis, and treatment of GCTs and study the clinical factors affecting survival as well as to determine whether the major changes over time in diagnostics, surgery, and chemotherapy have influenced these factors. This study’s assets are the 5decade-long study period in a single institute with a large, partly prospective patient series of histologically reconfirmed adult-type GCTs.
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evaluation of original pathology reports and clinical data in addition to consensus by a gynecologic oncologist and a gynecologic pathologist. Two cases of primary extraovarian tumors were excluded. After the reevaluation of original diagnoses, a total of 187 patients were eligible for analysis (Fig. 1). The study covers both retrospective and prospective patient groups. Since October 2007, patients with suspected or diagnosed GCT as well as those in follow-up (n = 97) have been recruited with their informed consent for a prospective long-term follow-up study with a structured interview on hormonal and reproductive factors and family cancer. If the patients were no longer involved in routine follow-up, they received an invitation for a similar interview and clinical examination with a vaginal scan every 5 years. For all patients, detailed data were collected from medical records for age, body mass index (BMI), menarcheal age, menopausal status, parity, use of hormonal therapy or oral contraceptives, history of infertility and second or family cancer, main symptoms, tumor characteristics (size, stage, presence of tumor rupture, ascites, residual tumor), endometrial pathology, treatment, and pathology reports. The follow-up information included details on follow-up visits performed at HUCH or other units, recurrences, and survival. Survival data were obtained from the Finnish national population register on December 27, 2012, and from death certificates including diagnosis of the cause of death from the Statistics Finland. The clinical data were collected into a database using FileMaker Pro 11.0v4 (FileMaker, Inc, Santa Clara, CA). To study the effects of improved diagnostics, surgical techniques, and chemotherapy, the data were divided into 2 groups according to the time of diagnosis: 1956Y1983 and 1984Y2012, corresponding to the ‘‘old’’ and ‘‘new’’ era, respectively. The new era is characterized by the introduction of platinum-based chemotherapy and improved staging surgery as well as increased use of vaginal ultrasonography and computed tomographic scans in our unit. Because many of the patients (n = 19) had a history of previous hysterectomy,
MATERIALS AND METHODS Patients The ethics committee of Helsinki University Central Hospital (HUCH) and the National Supervisory Authority for Welfare and Health approved the study. A total of 240 women were diagnosed with GCT in HUCH in 1956Y2012. Helsinki University Central Hospital is a tertiary hospital responsible for the cancer treatment of 1.5 million inhabitants in Southern Finland. An expert gynecologic pathologist (R.B.) reviewed all available histologic samples to confirm the diagnosis of GCT. Of the patients with no available sample (n = 14), a total of 3 cases were included in the study on the basis of a thorough
34
FIGURE 1. Flow chart of the patients included in the study. All patients with GCT diagnosed at HUCH from 1956 to 2012 were initially enrolled, histologically reevaluated, and divided into 2 eras according to the introduction of platinum-based chemotherapy in 1984. Altogether, 53 patients were excluded from the study. * 2014 IGCS and ESGO
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surgery was considered complete if no gynecological organs were left and incomplete if an adnexa and/or uterus were preserved. Fertility-sparing surgery was defined as the preservation of the uterus and 1 ovary in a patient younger than 45 years. The definition of staging surgery included cases where peritoneal biopsies and omental biopsy or omentectomy were performed. Adjuvant hormonal treatment was equivalent to a high-dose medroxyprogesterone acetate. Determination of tumor stage was based on the FIGO 2009 criteria.17 Recurrence was recorded only in patients having no residual tumor after surgery or after chemotherapy, the latter being dependent upon a clean computed tomographic
Factors of Survival in Adult-Type GCT
scan or a second-look operation. Otherwise, patients were not considered disease-free after primary treatment.
Statistical Analysis Statistical analysis was performed using JMP Pro 10.0.2 (SAS Institute Inc, Cary, NC). The Pearson W2 test or Fisher exact test was used to test associations between the groups. Continuous variables were analyzed for normal distribution with the Shapiro-Wilk test and compared with a parametric (Student t test) or a nonparametric test (Mann-Whitney) when appropriate. The survival curves and estimates were obtained using the Kaplan-Meier method, compared using the log-rank
TABLE 1. Clinical characteristics of the patients with GCT according to time of diagnosis
Characteristic (Patients With Data Available) Age, y (n = 187) G60 960 Menarche (n = 165) G14 Q14 Menopausal status (n = 184) Premenopausal Postmenopausal Parity (n = 185) Nulliparous Primiparous Multiparous Infertility (n = 178) Yes No HRT (n = 133) Yes No OC (n = 138) Yes No Initial symptoms (n = 186) Abnormal bleeding Abdominal pain Abdominal distension General symptoms Asymptomatic Preoperative imaging (n = 183) Ultrasonography Computed tomographic scan
1956Y1983 The Old Era
1984Y2012 The New Era
Total N = 187
n = 70
n = 117
n (%)
48 (68.6%) 22 (31.4%)
79 (67.5%) 38 (32.5%)
127 (67.9) 60 (32.1)
ns
24 (40.0%) 36 (60.0%)
64 (61.0%) 41 (39.0%)
88 (53.3) 77 (46.7)
0.01
27 (39.1%) 42 (60.9%)
46 (40.0%) 69 (60.0%)
73 (39.7) 111 (60.3)
ns
23 (33.3%) 16 (23.2%) 30 (43.5%)
41 (35.3%) 22 (19.0%) 53 (45.7%)
64 (34.6) 38 (20.5) 83 (44.9)
ns
7 (10.6%) 59 (89.4%)
20 (17.9%) 92 (82.1%)
27 (15.2) 151 (84.8)
ns
4 (10.5%) 34 (89.5%)
21 (22.1%) 74 (77.9%)
25 (18.8) 108 (81.2)
ns
9 (17.0%) 44 (83.0%)
48 (56.5%) 37 (43.5%)
57 (41.3) 81 (58.7)
G0.0001
40 (58.0%) 12 (17.4%) 12 (17.4%) 0 (0.0%) 5 (7.2%)
43 36 14 3 21
(36.7%) (30.8%) (12.0%) (2.6%) (17.9%)
83 (44.6) 48 (25.8) 26 (14.0) 3 (1.6) 26 (14.0)
0.005
104 (91.2%) 2 ( 1.8%)
115 (62.8) 2 (1.1)
G0.0001 ns
11 (15.9%) 0 (0.0%)
Difference Between the Eras, P
HRT, hormone replacement therapy; ns, not significant; OC, oral contraceptives.
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test, and displayed leaving minimum of 5 subjects at risk. The univariate and multivariate analyses were conducted with the Cox regression model; only significant variables in the univariate tests were included in the multivariate models. For stage I analysis, clinically relevant variables were included in the univariate and multivariate models. A P value of less than 0.05 was considered significant.
RESULTS Histological Reevaluation Adult GCT was histologically reconfirmed in 187 (77.9%) patients (Fig. 1). The revised diagnoses of the 40 (16.7%; 23% in the old era, 12% in the new era) tumors are presented in Supplementary Table 1 (available as Supplemental Digital Content at http://links.lww.com/IGC/A236). From original stage distribution, 15.8% (n = 31) of stage I, 2.3%
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(n = 3) of stage II, 53.3% (n = 8) of stage III, and 100.0% (n = 4) of stage IV tumors were excluded from the analysis.
Patient Characteristics The clinical characteristics of patients with GCT according to the 2 eras are summarized in Table 1. The mean age at diagnosis in the whole series was 52.9 years (range, 18Y87 years), and there was no significant difference between the eras. The median menarcheal age was 13 years (range, 9Y20 years) and was significantly lower in the new era (P = 0.02). The median BMI was 26 kg/m2 (range, 14.3Y45.3 kg/m2). The use of both oral contraceptives and hormone replacement therapy was more frequent in the new era, but only the use of oral contraceptives was significant (P G 0.0001). The presenting symptoms were most commonly menstrual cycle disturbances or postmenopausal bleeding in both eras (44.6%). Altogether, 114 women (61.0%) experienced abnormal bleeding patterns. Of all patients, 26 (14.0%) were
TABLE 2. Primary tumor characteristics of the patients with GCT according to time of diagnosis
Characteristic (Patients With Data Available) Tumor size (n = 179) G10 cm Q10 cm Tumor location (n = 187) Right ovary Left ovary Bilateral Ascites* (n = 166) Yes No Tumor rupture† (n = 180) Yes No Stage (n = 185) I II III Endometrial pathology (n = 157) Polyps Hyperplasia Carcinoma No pathology Histological subtype (n = 161) Follicular/trabeculoid Diffuse/sarcomatoid
1956Y1983 (The Old Era)
1984Y2012 (The New Era)
Total N = 187
n = 70
n = 117
n (%)
26 (39.4%) 40 (60.6%)
57 (50.4%) 56 (49.6%)
83 (46.4) 96 (53.6)
ns
33 (47.1%) 35 (50.0%) 2 (2.9%)
60 (51.3%) 54 (46.2%) 3 (2.6%)
93 (49.7) 89 (47.6) 5 (2.7)
ns
12 (17.9%) 55 (82.1%)
26 (26.3%) 73 (73.7%)
38 (22.9) 128 (77.1)
ns
15 (23.8%) 48 (76.2%)
49 (41.9%) 68 (58.1%)
64 (35.6) 116 (64.4)
0.016
60 (88.2%) 4 (5.9%) 4 (5.9%)
105 (89.7%) 9 (7.7%) 3 (2.6%)
165 (89.2) 13 (7.0) 7 (3.8)
ns
5 36 3 20
(7.8%) (56.2%) (4.7%) (31.3%)
17 (18.3%) 25 (26.9%) 8 (8.6%) 43 (46.2%)
19 (32.2%) 40 (67.8%)
42 (41.2%) 60 (58.8%)
22 61 11 63
Difference Between the Eras, P
(14.0) (38.9) (7.0) (40.1)
0.003
61 (37.9) 100 (62.1)
ns
*Positive cytology, n = 5. †Spontaneous or iatrogenic. ns, not significant.
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asymptomatic and diagnosed during routine gynecological examination or imaging procedures. In the new era, the proportion of asymptomatic patients was higher, whereas those with abdominal distension were fewer (P = 0.03). Of the 26 patients with abdominal distension, 24 had a large tumor (910 cm), 19 had ascites at the time of diagnosis, and 6 patients experienced tumor rupture.
Tumor Characteristics Tumor characteristics are reported in Table 2. The median tumor size was 10.0 cm (mean, 10.8 cm; range, 0.5Y30 cm). Ascites was present in 38 patients (22.9%) at the time of surgery, but cytology was positive only in 5 cases. Either spontaneous or iatrogenic tumor rupture occurred significantly more often in the new era (P = 0.02). Of all the 48 ruptures in the new era, 18 were spontaneous and 30 occurred during surgery. Twenty (41.7%) of these were laparoscopic procedures. The majority of the patients had stage I disease (165 cases, 89.2%) without significant variation over time. There were no stage IV cases present in the data.
Factors of Survival in Adult-Type GCT
Endometrial pathology occurred in 94 patients (59.9% of those evaluated), with a significant difference between the eras (P = 0.003): endometrial hyperplasia was less common and polyps were more common in the new era, whereas endometrial cancer occurred quite similarly between the 2 eras. Any other cancer before, at, or after GCT diagnosis was discovered in 20.9% of all patients with the available data, with no significant differences in the 2 eras. The most common other cancers were endometrial (n = 11, 6.7%) and breast (n = 9, 5.5%) cancer. History of cancer in a first-degree relative was found in 50.0%, with breast cancer being the most common (22.0%).
Treatment Characteristics All patients underwent surgical treatment (Table 3). The majority of the patients (78.0%) had complete surgery, and the presence of residual tumor was similar in both eras. Staging surgery and lymphadenectomy or lymph node biopsy were performed only in the new era (P G 0.001). Fertilitysparing surgery took place in 16.8% of cases. Surgery as the
TABLE 3. Treatment characteristics of primary GCT according to time of diagnosis
Characteristic (Patients With Data Available) Initial surgery (n = 186) Complete* Incomplete Staging surgery Lymphadenectomy† Residual tumor (n = 183) Yes No Treatment modality (n = 186) Surgery only Surgery + CT Surgery + RT Surgery + CT + RT Chemotherapy (n = 187) Nonplatinum-based CT Platinum-based CT Adjuvant hormonal therapy‡ (n = 187) Yes No Second-look operation (n = 187) Yes No
1956Y1983 The Old Era
1984Y2012 The New Era
Total (%)
n = 70
n = 117
n = 187
57 12 0 0
(82.6%) (17.4%) (0.0%) (0.0%)
88 (75.2%) 29 (24.8%) 52 (44.4%) 41 (35.3%)
3 (4.4%) 66 (95.6%)
3 (2.6%) 111 (97.4%)
42 7 11 9
145 41 52 41
(78.0) (22.0) (28.1) (22.2)
6 (3.3) 177 (96.7) 141 22 13 10
(75.8) (11.8) (7.0) (5.4)
Difference Between the Eras, P ns G0.0001 G0.0001 ns
G0.0001
(60.9%) (10.1%) (15.9%) (13.0%)
99 (84.6%) 15 (12.8%) 2 (1.7%) 1 (0.9%)
16 (22.9%) 0 (0.0%)
1 (0.9%) 15 (12.8%)
17 (9.1) 15 (8.0)
G0.0001
12 (17.1%) 58 (82.9%)
1 (0.9%) 116 (99.2%)
13 (6.9) 174 (93.1)
G0.0001
7 (10.0%) 63 (90.0%)
11 (9.4%) 106 (90.6%)
18 (9.6) 169 (90.4)
ns
*No gynecological organs (adnexa or uterus) left after initial treatment. †Lymph node biopsy or lymphadenectomy. ‡A high-dose medroxyprogesterone acetate. CT, chemotherapy; ns, not significant; RT, radiotherapy.
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only treatment became more common in the new era. Adjuvant treatment was given to a total of 45 patients, including chemotherapy (n = 32), adjuvant hormonal treatment (n = 13), and radiotherapy (n = 23), with some of the treatment methods overlapping. In the new era, pelvic radiotherapy was given to 3 patients, once solely for GCT in 1984 and twice for GCT and a simultaneous endometrial carcinoma. Similarly, only 1 elderly patient with inoperable GCT received hormonal adjuvant therapy in the new era. Postoperative platinum-based chemotherapy was given to 15 patients in the new era, of whom 5 had stage IC and 6 stage IIYIII diseases. Second-look operation was common from 1970 to 1998 and was performed on 10% of all patients in the series.
Outcomes and Survival Analysis The mean follow-up period was 15.6 years (median, 13.7 years; range, 0.01Y50.7 years) in the total study group. The follow-up was significantly longer in the old era (mean, 22.1; median, 22.4; range, 0.7Y50.7) than in the new era (mean, 11.5 years; median, 10.3; range, 0.01Y27.8; P G 0.0001), as expected. A total of 24 patients (23.8%) had less than 5 years of follow-up data in the new era. At the end of the follow-up, 113 patients (60.4%) were alive, 27 (14.4%) had died of GCT, and 46 (24.6%) had died of other causes. One patient was lost to follow-up. In total, 127 patients (68.6%) were free of the disease during the whole study period. Recurrence was observed in a total of 54 patients (29.2%). In the old era, the rate of recurrence was 35.7%, whereas the rate was 25.2% in the new era (P = 0.11). The median time to the first recurrence was 7.0 years (range,
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1.0Y32.5). A total of 9 patients were alive with recurrence at the end of the follow-up. In the whole series, the overall 5-, 10-, and 20-year survival rates were 94.4%, 87.1%, and 67.1%, respectively (Supplementary Fig. 1, available as Supplemental Digital Content at http://links.lww.com/IGC/A237). The GCT-specific 5-, 10-, and 20-year survival rates were 96.7%, 91.8%, and 87.1%. In the old era, GCT-specific 5-, 10-, and 20-year survival rates were 95.6%, 88.1%, and 79.8% as well as 97.2%, 94.8%, and 94.8% in the new era, respectively. In the univariate Cox regression analysis, decreased overall survival was associated with patient age older than 60 years, old era, menarcheal age older than 14 years, postmenopausal status, presence of symptoms, advanced stage, complete surgery, presence of residual tumor, and use of hormonal adjuvant therapy, whereas history of infertility and use of oral contraceptives were associated with a more favorable outcome (data not shown). In the multivariate analysis, patient age older than 60 years, old era, advanced stage, and presence of residual tumor were the factors that remained significant. The GCT-related deaths were associated with diagnosis in the old era as well as patient age older than 60 years, tumor size greater than 10 cm, advanced stage, presence of residual tumor after initial surgery, and use of hormonal adjuvant therapy (Table 4). Patient age was also significant when analyzed as a continuous variable, but tumor size was not (data not shown). The use of oral contraceptives and history of infertility before diagnosis improved GCT-related survival. However, in the multivariate analysis, only higher stage (II-III vs I) remained significant. In addition, KaplanMeier curves illustrate survival outcomes (Fig. 2). The use
TABLE 4. The Cox regression models for GCTYspecific survival Prognostic Factors in the Multivariate Analysis
GCT-Specific Survival Prognostic Factors in the Univariate Analysis Factor Infertility Use of OC Stage IIYIII vs stage I Residual tumor Hormonal adjuvant Age 960 y Old era Tumor size Q10 cm
HR
95% CI
P
HR
95% CI
P
0.20 0.33 16.19 10.98 3.64 2.82 2.68 2.43
0.01Y0.93 0.08Y0.99 6.26Y43.42 3.09Y31.08 1.33Y8.52 1.16Y6.73 1.07Y7.63 1.02Y6.68
0.04 0.05 G0.0001 0.0009 0.02 0.02 0.04 0.04
0.80 0.85 10.51 1.71 3.33 1.07 2.17 3.10
0.04Y5.56 0.16Y3.77 1.65Y69.48 0.18Y13.97 0.80Y12.37 0.20Y4.90 0.40Y18.44 0.75Y21.07
ns ns 0.01 ns ns ns ns ns
Prognostic Factors in the Multivariate Analysis
Stage I GCT-Specific Survival Prognostic Factors in the Univariate Analysis Factor
HR
95% CI
P
HR
95% CI
P
Age 960 y Stage IB or C vs stage IA Tumor size 910 cm
2.54 1.96 1.85
0.64Y8.72 0.69Y5.38 0.62Y6.79
ns ns ns
2.37 1.56 1.72
0.60Y8.18 0.49Y4.79 0.54Y6.50
ns ns ns
CI, confidence interval; HR, hazard ratio; OC, oral contraceptives.
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Factors of Survival in Adult-Type GCT
FIGURE 2. Kaplan-Meier curves of GCT-specific survival according to time of diagnosis (A), age at diagnosis (B), tumor size (C), tumor stage (D), treatment with platinum versus nonplatinum-based chemotherapy (E), and presence of residual tumor (F). All curves are illustrated leaving a minimum of 5 patients at risk at the end of the horizontal axis. of platinum-based chemotherapy (Fig. 2E) and lack of symptoms were associated with a more favorable outcome but could not be included in the Cox regression analyses because of the absence of GCT-associated deaths in these groups. To further study the effects of platinum-based treatment, we conducted a univariate Cox regression analysis after excluding all patients treated with chemotherapy and found no
statistically significant difference in GCT-related survival between the new and old era groups (data not shown). In a separate analysis including only stage I tumors, there were no significant variables associated with GCTspecific survival (Table 4). Also, there were no differences in GCT-specific or overall survival related to BMI, parity, history of second or family cancer, use of hormone replacement
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International Journal of Gynecological Cancer
Bryk et al
therapy before or after diagnosis, endometrial pathology, staging surgery, lymphadenectomy, or tumor rupture.
DISCUSSION The long natural course of GCT requires decades of follow-up to provide reliable information on its behavior, especially on survival.12 The mean follow-up time of 15.6 years, or 187 months, in our study is remarkably longer than that in other recent publications.2,6,12,13 Even for the new era patients alone, the mean follow-up time of 11.5 years was reached. Only 1 patient was lost to follow-up 32 years after the diagnosis. The histological reevaluation excluded more than 20% of original diagnoses and changed stage distribution notably by removing more than 50% of stage III and all stage IV tumors from the study. This demonstrates the need for histological reevaluation to obtain reliable data, even in a single-institute study. Furthermore, the distinction between adult- and juveniletype GCTs is crucial, and these tumors should always be analyzed separately. The analysis of forkhead box protein L2 (FOXL2) mutation status is a promising new tool for accurate GCT diagnosis in difficult cases.18 We studied a large number of clinical prognostic factors related to GCT survival for more than 5 decades in relation to major developments in diagnostics, surgery, and chemotherapy. By performing a short structured interview in the prospective part of the study on both new and old era patients, we were able to fill in incomplete data on hormonal and reproductive history and evaluate the effects of oral contraceptives and postmenopausal hormone therapy on GCT prognosis. These have not been previously studied, although Boyce et al19 found in their epidemiological work that the use of oral contraceptives decreased the risk for developing GCT. There is also evidence linking infertility but not infertility treatments with GCT.4 The study’s infertility rate of 15.1% does not differ from population-based reference data,20 and in univariate analyses, infertility had a positive effect on survival, which was independent of the era. This suggests that hormonal therapy given for contraceptive use, infertility, postmenopausal symptoms, or treatment of bleeding disturbances is not harmful in terms of GCT-related survival. Overall, the clinical characteristics of patients with GCT have not changed over time. The earlier menarcheal age evident in the new era is a well-known phenomenon.21 Interestingly, in our data, tumor ruptures increased over time. A possible explanation is the growing number of laparoscopic procedures and, in some of the cases, an urgent surgery performed due to acute symptoms and without initial suspicion of malignancy. However, tumor rupture did not affect survival. In most studies, stage has remained the most important prognostic factor. This was confirmed in our series. Furthermore, there were no statistically significant clinical prognostic factors in stage I subanalysis, underscoring the need for molecular prognostic factors. Recently, we reported high-level nuclear atypia and high-level protein expression of GATA binding protein 4 (GATA4) as prognostic factors for GCT recurrence and survival, also in early-stage GCTs, in a subcohort of this patient series.22 Similarly to the study of Ayhan et al,6 we found that patient age older than 60 years was a significant factor in
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univariate but not in multivariate analysis, also when analyzed as a continuous variable. Tumor size had no independent effect on survival. The number of patients with residual disease was very small, so reliable conclusions of its prognostic value cannot be made. Conservative or fertility-sparing surgery did not affect outcome negatively. These results confirm those from earlier studies.2,6,7 Lymphadenectomy or lymph node biopsy was not of prognostic value in our series, as also Park et al8 and Mangili et al12 have reported. The first platinum-based chemotherapy in this study was administered in 1984, and diagnosis in the old era was associated with poorer outcome. Furthermore, the use of platinum-based treatment had a more favorable outcome when compared with nonplatinum treatment. Benefits of platinum-based treatment have been reported in several studies,8,10,23 and similar to our results, Savage et al23 found no response to nonplatinum-based chemotherapeutic agents or hormonal adjuvant therapy in the management of advanced GCT. Currently, BEC-regimen (bleomycin, etoposide, carboplatin) is the first-line chemotherapy at our institution, followed by paclitaxel-carboplatin as the secondline treatment. The survival rates in our study, especially in the new era, were among the highest in the literature, further confirming the overall favorable prognosis of GCTs. However, these tumors are known to develop late recurrences, also in the earlystage disease. Recurrence rates have varied between 10% and 34% as well as reached 29% in our study with confirmed diagnosis of GCT. The long time span of our study is both a strength and a weakness. We sought to take into account the development of diagnostic and treatment methods that might have affected the outcome. The inclusion of both retrospective and prospective data might have caused a potential bias because detailed information on, for example, hormonal therapy is focused on the latter group. Taken together, the accurate histological diagnosis of GCT is essential. In this large series of mostly early-stage GCTs, tumor stage remains the single most important prognostic factor affecting GCT-specific survival. The prognosis of GCT nowadays is excellent. Conservative or fertility-sparing surgery does not compromise survival, and the modern era with better diagnostics and treatments, including platinum-based chemotherapy, is associated with a more favorable outcome. Nevertheless, one-third of patients still develop disease recurrence, which calls for a long clinical follow-up and further detailed studies focusing on recurrent tumors.
ACKNOWLEDGMENTS The authors thank Ms Teija Karkkulainen, Mr Qiu Ge, and Mrs Anne Reijula for their excellent technical assistance.
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